Non-medullary thyroid cancer (TCA), the most common type of endocrine malignancy, accounts for most deaths due to endocrine cancers. Although the majority of TCAs are successfully managed with surgery and radioactive iodine (I-131) ablative therapy, the mortality associated with this disease has remained stable over the years because these therapies are not effective for clinically aggressive tumors, which have accelerated patterns of growth and/or fail to trap iodine efficiently. This group consists of poorly-differentated and anaplastic TCAs, but also includes certain sub-groups of well-differentiated TCAs. The loss of iodine trapping ability by the malignant thyrocyte may be correlated with other cellular and molecular events that accompany de-differentiation. Our goal is to study the molecular events accompanying the natural history of clinically aggressive TCA and the response of various molecular markers to standard therapeutic intervention(s). Preoperative diagnostic methods include aspiration cytology, ultrasonography, thyroid scanning with I-131 and/or other radionuclides, and suppression therapy with L- thyroxine. Specific issues include: (i) optimization of methods of diagnostic scanning in TCA and serum thyroglobulin measurement to diagnose tumor recurrence, (ii) refinement of already established methods of administering I-131 therapy to improve the risk/benefit ratio, (iii) PCR-based detection and quantification of thyroid-specific mRNAs (e.g. thyroglobulin mRNA and mRNAs for other markers) in thyrocytes circulating in peripheral blood, (iv) analysis of mutations in genes involved in TCA growth, apoptosis, and mitotic cycle regulation, such as the thyrotropin receptor, ras, p53, Fas/Fas ligand, and ret/PTC in primary and metastatic thyroid tumors, and (v) establishment of immortalized cell lines from TCAs for in vitro studies. The relationship between the existence or absence of markers of differentiation and mutations in growth-relevant genes, and the clinical behavior of TCA will help define the pathways responsible for thyrocyte growth and differentiation, and guide the development of new therapeutic strategies to attack clinically aggressive TCAs by reverting them to a more benign differentiated phenotype.